The main hypothesis of this proposal is that the spectrum of disease associated with L. braziliensis infection is a reflection not only of whether an individual has mounted an effector immune response against the parasite, but, whether this effector response is appropriately modulated response. For over 25 years we have conducted laboratory and field based studies in leishmaniasis and have shown that while a type 1 immune response is critical for protection, an exaggerated inflammatory response as observed in cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML) determine patology. In contrast, up to 75% of L. braziliensis infected individuals, which have a modulated immune response, will remain without disease. The major aims are: 1) Determine whether individuals with subclinical L. braziliensis infection (SC) have an appropriately modulated immune response, and whether patients with clinically symptomatic disease have defective regulatory mechanisms. We will evaluate the role of IL-27 and Treg cells in modulating the immune response and determine the mechanisms responsible for the failure of IL-10 to down regulate immune response in CL and ML. Leucocytes from SC, CL and ML will be used for these studies. We will use techniques such as intracellular cytokine staining coupled with flow cytometer-based analyses of lymphocyte proliferation, and studies derived from sorted, purified cell populations, to determine, in previously unattainable detail, the function of these cell populations. 2) Determine the specific mechanisms of tissue destruction in CL and ML. The ulcerative lesions that develop in CL and ML are associated with a strong inflammatory response. We will measure TNF-a receptor expression, apoptosis chemokines involved in the leukocyte recruitment, metalloproteinases, and IL-17. 3) Determine memory T cell responses after spontaneous or drug induced cure of subclinical or symptomatic human tegumentary leishmaniasis. We will evaluate lymphocyte proliferation and cytokine production to selected recombinant leishmania antigens. In individuals with past history of SC L. braziliensis and L. chagasi infection as well as in patients cured of CL, ML, and VL. Futhermore the development of central memory and effector memory T cells will be evaluated. These studies will elucidate immune mechanisms that could inspire the development of novel immune based strategies to be used as immunotherapy.